Diabetic retinopathy is one of the leading causes of blindness in the United States and vascular permeability resulting in macular edema is highly associated with vision loss. Breakdown of the normal blood-retinal barrier is believed to disrupt normal retinal neuronal function. Research from the laboratory of the co-PI has demonstrated that growth factors such as vascular endothelial growth factor, which are elevated in the eyes of patients with diabetes, breakdown the blood-retinal barrier by altering tight junction proteins. Conversely, glucocorticoids have the opposite effect and induce barrier properties by stimulating the synthesis and assembly of tight junction proteins. Glucocorticoids cannot be given systemically to patients with diabetes because of their glucose elevating effects and local treatment is invasive and may include side effects such as glaucoma and cataract formation. Therefore, a need exists to identify novel compounds that specifically induce vascular barrier properties without these side effects. In order to identify these compounds we will partner with Dr. Charles Smith, Director of the Drug Discovery Core Facility at the Penn State College of Medicine to screen a chemical library for compounds that induce endothelial barrier properties. Screening methods have been established and preliminary data have already identified candidate compounds that are effective in reducing dextran flux across endothelial monolayers. Specific aim 1 will use a series of screens to identify compounds that induce vascular barrier properties but that do not induce gluconeogenesis in hepatocytes. Specific aim 2 will investigate the mechanism of action of lead compounds. Experiments will reveal whether the glucocorticoid receptor is necessary in the action of the candidate compound and the effect of the compound on tight junction protein synthesis and assembly will be examined. These experiments will provide novel, lead compounds that will be further developed to treat macular edema in diabetic retinopathy.